AB0050 ALTERED NAMPT, ADIPOKINE AND CYTOKINE LEVELS CHARACTERIZE MONOCYTE ACTIVITY AND CORRELATE WITH DISEASE SEVERITY IN OSTEOARTHRITIS
Authors: F. Motta, B. Durante, C. Pandolfo, C. Selmi, A. Sica
Journal: Annals of the Rheumatic Diseases (2022)

Background Osteoarthritis (OA) is a chronic, debilitating, aging-associated disease (1), characterized by chronic low-grade inflammation, the underlying mechanisms of which are poorly understood (2). Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme in the NAD + salvage pathway, in charge of maintaining cellular homeostasis through redox reactions. NAD + promotes the expression of sirtuin-1 (SIRT1), which regulates the mobilization of myeloid-derived suppressor cells from the bone marrow. Extracellular eNAMPT, the secreted form of NAMPT also known as visfatin, is an adipokine involved in OA pathogenesis (3,4). Objectives We aim to analyse the cytokine and adipokine profile and the role of i- and eNAMPT in OA-related inflammation. Methods Peripheral blood and, whenever possible, synovial fluid from knee joint were collected from patients with OA older than 50 years. Samples from subjects without OA older than 50 (non-OA&gt;50y) and younger than 30 (non-OA&lt;30y) were used as controls. Serum, plasmatic, and synovial fluid adipokines and cytokines were measured by ELISA. Peripheral blood mononuclear cells were purified with Ficoll gradient and monocytes were selected with anti-human CD14 microbeads; RNA was extracted for polymerase chain reaction for NAMPT, SIRT1 and pro/anti-inflammatory cytokines. Monocyte intracellular NAD + was measured at baseline and 1 hour after nicotinamide (a NAMPT substrate and precursor of NAD + ) supplementation. Results were correlated with clinical data. Results Peripheral blood was obtained from 51 patients with OA (19 with synovial fluid also), 44 from non-OA&gt;50y, and 35 from non-OA&lt;30y controls. Plasmatic chemerin and leptin were higher in OA patients, visfatin was higher in OA and in non-OA&gt;50y group (p&lt;0.01 for all analyses). Plasmatic and synovial levels of leptin and resistin were correlated (p&lt;0.001, r=0.6 for both comparisons); synovial leptin and resistin correlated with synovial IL-6, VEGF, and TNFα and these were higher in polyarticular OA (vs monoarticular, p=0.01 and p=0.03, respectively) and in OA with more severe Kellgren-Lawrence score (p=0.003 and p=0.03, respectively). Monocyte expression of NAMPT and anti-inflammatory cytokines IL-10 and Arginase-1 was increased in non-OA&lt;30y controls compared to OA patients and non-OA&gt;50y subjects (p&lt;0.05 for all analyses). At baseline, monocyte intracellular NAD + content was higher in the non-OA&gt;50y cohort; after niacin supplementation, non-OA&gt;50y subjects had the highest content, whereas OA patients had higher NAD levels than at baseline, but significantly lower than non-OA&gt;50y controls (Figure 1). Figure 1. Monocyte NAD + content at baseline and 1 hour after nicotinamide supplementation. *p&lt;0.05 **p&lt;0.01 ****p&lt;0.0001. Conclusion A specific plasmatic and synovial adipokine signature characterizes OA and patients with more severe disease. In monocytes there is a age-related reduction of iNAMPT and anti-inflammatory cytokine expression, whereas eNAMPT is higher in elderly compared with younger subjects. In non-OA&gt;50y subjects there might be an increase of iNAMPT activity which leads to NAD + production, while in OA patients this mechanism seems to be impaired and can be only partially enhanced by nicotinamide supplementation, leading to reduced intracellular redox efficiency. These results suggest that NAMPT activity might be a key component of the mechanisms underlying inflammation in OA patients. References [1]Hunter DJ, et al. Lancet. 2019 Apr 27;393(10182):1745-1759. [2]Motta F, et al. Front Immunol. 2020 Oct 29;11:576134. [3]Travelli C, et al. Cancer Res. 2019 Apr 15;79(8):1938-1951. [4]Liao L, et al. J Bone Miner Metab. 2016 Sep;34(5):485-90. Disclosure of Interests Francesca Motta Consultant of: Thermo Fisher, Barbara Durante: None declared, Chiara Pandolfo: None declared, Carlo Selmi Speakers bureau: AbbVie, Amgen, Alfa-Wassermann, Biogen, Celgene, Eli-Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Sanofi-Genzyme, Consultant of: AbbVie, Amgen, Alfa-Wassermann, Biogen, Celgene, Eli-Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Sanofi-Genzyme, Grant/research support from: AbbVie, Amgen, Janssen, Pfizer, Antonio Sica: None declared